PLASMIN SYSTEM AND IGF FUNCTION IN OSTEOSARCOMA

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Insulin-like growth factors (IGFs) are produced by and affect nearly all types of cells, including bone cells. IGFs exist in blood and in the interstitial space bound to specific IGF-binding proteins (IGFBPs). IGFBPs can inhibit the action of IGFs in normal and neoplastic bone by forming biologically inactive complexes with IGFS. The physiological mechanism(s) by which IGFs are released from IGFBP remains unclear. Therefore, the major goal of this project is to understand how paracellular proteases affect IGF action. Osteosarcoma cells secrete plasminogen activators which activate plasminogen to plasmin (plasmin system). Preliminary experiments conducted with media conditioned by osteosarcoma cells establish an involvement of plasmin system in IGF activation. The intent of this project is to extend these data and demonstrate that the PA-plasminogen-plasmin enzymatic cascade operates also at the cellular level. To this end, we propose to use human osteosarcoma cell lines as our model system. Parameters of IGF action, e.g. cell binding, growth and differentiation, will be determined in regard to regulation of the IGF-BP complex by the plasmin system Studies of the various steps in the dissociation of IGFs from IGFBP to IGF will be performed. During the course of these investigations, we will test the hypothesis that the site of IGF activation is at the cell surface or its immediate vicinity. Finally, the interactions among the plasmin system, IGF, and IGFBP as regards to the gene expression and peptide secretion, will also be established. lbe findings from this proposed research will provide a basic insight into the regulation of IGF action applicable not only to neoplastic cell types but normal cells as well.